Method of stimulating the motility of the gastrointestinal system using growth hormone secretagogues

ABSTRACT

The present invention relates to a method of stimulating the motility of the gastrointestinal system in a subject in need thereof, wherein the subject suffers from maladies (i.e., disorders or diseases) of the gastrointestinal system. The method comprises administering to a subject in need thereof a therapeutically effective amount of a growth hormone secretagogue compound or a pharmaceutically acceptable salt, hydrate or solvate thereof. The growth hormone secretagogue can be co-administered with a laxative, a H 2  receptor antagonist, a serotonin 5-HT 4  agonist, an antacid, an opioid antagonist, a proton pump inhibitor, a motilin receptor agonist, dopamine antagonist, a cholinergic agonist, a cholinesterase inhibitor, somatostatin, octreotide, or any combination thereof.

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 60/600,959 filed Aug. 12, 2004, the disclosure of which isincorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Gastrointestinal (GI) motility is a coordinated neuromuscular processthat transports nutrients through the digestive system. C. Scarpignato,“Pharmacological Stimulation of Gastrointestinal Motility: Where We AreAnd Where Are We Going?” Dig. Dis., 15: 112 (1997). Impaired (i.e.,slowed) motility of the gastrointestinal system, which can be involvedin gastroesophageal reflux disease, gastroparesis (e.g., diabetic andpostsurgical), irritable bowel syndrome and constipation, is one of thelargest health care burdens of industrialized nations. S. D. Feighner etal., “Receptor for Motilin Identified in the Human GastrointestinalSystem,” Science, 284: 2184-2188 (Jun. 25, 1999).

In view of the above, an effective, physiological way to stimulatemotility of the gastrointestinal system is highly desirable.

SUMMARY OF THE INVENTION

The present invention relates to a method of stimulating the motility ofthe gastrointestinal system in a subject in need thereof, wherein thesubject suffers from maladies (i.e., disorders or diseases) of thegastrointestinal system. The method comprises administering to a subjectin need thereof a therapeutically effective amount of a growth hormonesecretagogue compound or a pharmaceutically acceptable salt, hydrate orsolvate thereof.

In one embodiment, stimulation of gastrointestinal motility is used in amethod of treating opioid induced constipation in a subject in needthereof comprising administering a therapeutically effective amount of agrowth hormone secretagogue compound or a pharmaceutically acceptablesalt, hydrate or solvate thereof. In one embodiment, the subject isusing opioids for post-surgical pain management. In another embodiment,the subject is using opioids for chronic pain management. Suitableopioids included, but are not limited to, percocet, morphine, vicoden,methadone, oxycodone and fentanyl. In a particular embodiment, thegrowth hormone secretagogue is represented by Formulas I-V, or apharmaceutically acceptable salt, hydrate or solvate thereof.

In another embodiment, stimulation of gastrointestinal motility is usedin a method of treating diabetes related gastroparesis in a subject inneed thereof comprising administering a therapeutically effective amountof a growth hormone secretagogue compound. In a particular embodiment,the growth hormone secretagogue is represented by Formulas I-V, or apharmaceutically acceptable salt, hydrate or solvate thereof.

In a further embodiment, stimulation of gastrointestinal motility isused in a method of treating gastroesophageal reflux disease (GERD) in asubject in need thereof comprising administering a therapeuticallyeffective amount of a growth hormone secretagogue compound. In aparticular embodiment, the growth hormone secretagogue is represented byFormulas I-V, or a pharmaceutically acceptable salt, hydrate or solvatethereof. In a particular embodiment, the gastroesophageal reflux diseaseis nocturnal gastroesophageal reflux disease.

In yet another embodiment, stimulation of gastrointestinal motility isused in a method of treating irritable bowel syndrome (IBS) in a subjectin need thereof comprising administering a therapeutically effectiveamount of a growth hormone secretagogue compound. In a particularembodiment, the growth hormone secretagogue is represented by FormulasI-V, or a pharmaceutically acceptable salt, hydrate or solvate thereof.In one embodiment, the irritable bowel syndrome isconstipation-predominant irritable bowel syndrome. In anotherembodiment, the irritable bowel syndrome is alternatingconstipation/diarrhea irritable bowel syndrome.

In one embodiment, stimulation of gastrointestinal motility is used in amethod of treating constipation in a subject in need thereof comprisingadministering a therapeutically effective amount of a growth hormonesecretagogue compound. In a particular embodiment, the growth hormonesecretagogue is represented by Formulas I-V, or a pharmaceuticallyacceptable salt, hydrate or solvate thereof.

In one embodiment, stimulation of gastrointestinal motility is used in amethod of treating post-operative ileus in a subject in need thereofcomprising administering a therapeutically effective amount of a growthhormone secretagogue compound. In a particular embodiment, the growthhormone secretagogue is represented by Formulas I-V, or apharmaceutically acceptable salt, hydrate or solvate thereof.

In a particular embodiment, the growth hormone secretagogue isrepresented by the structural Formula I:

wherein:

R¹ is hydrogen, or C₁₋₆-alkyl optionally substituted with one or morearyl or hetaryl;

a and d are independently 0, 1, 2 or 3;

b and c are independently 0, 1, 2, 3, 4 or 5, provided that b+c is 3, 4or 5;

D is R²—NH—(CR³R⁴)_(e)—(CH₂)_(f)-M-(CHR⁵)_(g)—(CH₂)_(h)—

wherein:

R², R³, R⁴ and R⁵ are independently hydrogen or C₁₋₆ alkyl optionallysubstituted with one or more halogen, amino, hydroxyl, aryl or hetaryl;or

R² and R³ or R² and R⁴ or R³ and R⁴ can optionally form—(CH₂)_(i)—U—(CH₂)_(j)—, wherein i and j are independently 1 or 2 and Uis —O—, —S— or a valence bond;

h and f are independently 0, 1, 2, or 3;

g and e are independently 0.0 or 1;

M is a valence bond, —CR⁶══—CR⁷—, arylene, hetarylene, —O— or —S—;

R⁶ and R⁷ are independently hydrogen, or C₁₋₆-alkyl optionallysubstituted with one or more aryl or hetaryl;

G is —O—(CH₂)_(k)—R⁸,

J is —O—(CH₂)_(l)—R¹³,

wherein:

R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ independently arehydrogen, halogen, aryl, hetaryl, C₁₋₆-alkyl or C₁₋₆-alkoxy;

k and l are independently 0, 1 or 2;

E is —CONR¹⁸R¹⁹, —COOR¹⁹, —(CH₂)_(m)—NR¹⁸SO₂R²⁰, —(CH₂)_(m)—NR¹⁸—COR²⁰,—(CH₂)_(m)—OR¹⁹, —(CH₂)_(m)—OCOR²⁰, —CH(R¹⁸)R¹⁹,—(CH₂)_(m)—NR¹⁸—CS—NR¹⁸R²¹ or —(CH₂)_(m)—NR¹⁸—CO—NR¹⁹R²¹; or

E is —CONR²²NR²³R²⁴, wherein R²² is hydrogen, C₁₋₆-alkyl optionallysubstituted with one or more aryl or hetaryl, or aryl or hetaryloptionally substituted with one or more C₁₋₆-alkyl; R²³ is C₁₋₆-alkyloptionally substituted with one or more aryl or hetaryl, or C₁₋₇-acyl;and R²⁴ is hydrogen, C₁₋₆-alkyl optionally substituted with one or morearyl or hetaryl; or aryl or hetaryl optionally substituted with one ormore C₁₋₆-alkyl; or

R²² and R²³ together with the nitrogen atoms to which they are attachedcan form a heterocyclic system optionally substituted with one or moreC₁₋₆-alkyl, halogen, amino, hydroxyl, aryl or hetaryl; or

R²² and R²⁴ together with the nitrogen atoms to which they are attachedcan form a heterocyclic system optionally substituted with one or moreC₁₋₆-alkyl, halogen, amino, hydroxyl, aryl or hetaryl; or

R²³ and R²⁴ together with the nitrogen atom to which they are attachedcan form a heterocyclic system optionally substituted with one or moreC₁₋₆-alkyl, halogen, amino, hydroxyl, aryl or hetaryl;

wherein m is 0, 1, 2 or 3,

R¹⁸, R¹⁹ and R²¹ independently are hydrogen or C₁₋₆-alkyl optionallysubstituted with halogen, —N(R²⁵)R²⁶, wherein R²⁵ and R²⁶ areindependently hydrogen or C₁₋₆ alkyl; hydroxyl, C₁₋₆-alkoxy,C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylcarbonyloxy or aryl; or R¹⁹ is

wherein

Q is —CH< or —N<,

K and L are independently —CH₂—, —CO—, —O—, —NR²⁷— or a valence bond,where R²⁷ is hydrogen or C₁₋₆ alkyl;

n and o are independently 0, 1, 2, 3 or 4;

R²⁰ is C₁₋₆ alkyl, aryl or hetaryl;

or a pharmaceutically acceptable salt thereof;with the proviso that if M is a valence bond then E is —CONR²²NR²³R²⁴.

The compounds of Formula I are fully described in U.S. Pat. No.6,303,620 to Hansen, et al., the entire content of which is herebyincorporated by reference.

In another embodiment, the growth hormone secretagogue of Formula I ismore specifically represented by the structural Formula II:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

The compounds of Formula II are fully described in U.S. Pat. No.6,303,620 to Hansen, et al., the entire content of which is herebyincorporated by reference.

In yet another embodiment, the growth hormone secretagogue isrepresented by the structural Formula III:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

The compound of Formula III is fully described in U.S. Pat. No.6,303,620 to Hansen, et al., the entire content of which is herebyincorporated by reference. The chemical name of the compound of FormulaIII is2-Amino-N-{(1R)-2-[3-benzyl-3-(N,N′,N′-trimethylhydrazinocarbonyl)piperidin-1-yl]-1-((1H-indol-3-yl)-2-oxoethyl}-2-methylpropionamide,and is referred to herein as RC-1291.

In a specific embodiment, the growth hormone secretagogue is representedby the structural Formula IV:

wherein

R¹ is hydrogen or C₁₋₆-alkyl;

R² is hydrogen or C₁₋₆-alkyl;

L is

wherein

R⁴ is hydrogen or C₁₋₆ alkyl;

p is 0 or 1;

q, s, t, u are independently 0, 1, 2, 3, or 4;

r is 1;

the sum q+r+s+t+u is 0, 1, 2, 3, or 4;

R⁹, R¹⁰, R¹¹, and R¹² are independently hydrogen or C₁₋₆ alkyl;

Q is >N—R¹³ or

wherein:

o is 0, 1 or 2;

T is —N(R¹⁵)(R¹⁶) or hydroxyl;

R¹³, R¹⁵, and R¹⁶ are independently hydrogen or C₁₋₆ alkyl;

R¹⁴ is hydrogen, aryl or hetaryl;

Or L is

wherein

p is 0 or 1;

q, s, t, u are independently 0, 1, 2, 3, or 4;

r is 0 or 1;

the sum q+r+s+t+u is 0, 1, 2, 3, or 4;

R⁹, R¹⁰, R¹¹, and R¹² are independently hydrogen or C₁₋₆ alkyl;

Q is >N—R¹³ or

wherein

o is 0, 1, or 2;

T is —N(R¹⁵)(R¹⁶) or hydroxyl;

R¹³, R¹⁵, and R¹⁶ are independently from each other hydrogen or C₁₋₆alkyl;

R¹⁴ is hydrogen, aryl, or hetaryl;

G is —O—O(CH₂)—R¹⁷,

wherein:

R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ independently are hydrogen, halogen, aryl,hetaryl, C₁₋₆-alkyl or C₁₋₆-alkoxy;

K is 0, 1 or 2;

J is —O—(CH₂)_(l)—R²²,

wherein:

R²², R²³, R²⁴, R²⁵ and R²⁶ independently are hydrogen, halogen, aryl,hetaryl, C₁₋₆-alkyl or C₁₋₆-alkoxy;

l is 0, 1 or 2;

a is 0, 1, or 2;

b is 0, 1, or 2;

c is 0, 1, or 2;

d is 0 or 1;

e is 0, 1, 2, or 3;

f is 0 or 1;

R⁵ is hydrogen or C₁₋₆-alkyl optionally substituted with one or morehydroxyl, aryl or hetaryl;

R⁶ and R⁷ are independently hydrogen or C₁₋₆-alkyl, optionallysubstituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;

R⁸ is hydrogen or C₁₋₆-alkyl, optionally substituted with one or morehalogen, amino, hydroxyl, aryl, or hetaryl;

R⁶ and R⁷ or R⁶ and R⁸ or R⁷ and R⁸ can optionally form—(CH₂)_(i)—U—(CH₂)_(j)—, wherein i and j independently are 1, 2 or 3 andU is —O—, —S—, or a valence bond;

M is arylene, hetarylene, —O—, —S— or —CR²⁷═CR²⁸—;

R²⁷ and R²⁸ are independently hydrogen or C₁₋₆-alkyl, optionallysubstituted with one or more aryl or hetaryl;

or a pharmaceutically acceptable salt thereof.

The compounds of Formula IV are fully described in PublishedInternational Application No. WO 00/01726 to Peschke, et al., the entirecontent of which is hereby incorporated by reference.

In another embodiment, the growth hormone secretagogue of Formula IV ismore specifically represented by the structural Formula V:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

The chemical name of the compound of Formula V is(2E)-5-Amino-5-methylhex-2-enoic acidN-((1R)-1-{N-[(1R)-1-benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(biphenyl-4-yl)ethyl)-N-methylamide,referred to herein as RC-1139.

The compound of Formula V is fully described in Published InternationalApplication No. WO 00/01726 to Peschke, et al., the entire content ofwhich is hereby incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a bar graph of percentage of gastric emptying for normal ratsadministered saline or RC-1139 at a dose of 0.25 mg/kg, 1.0 mg/kg or 2.5mg/kg. The results demonstrate a statistically significant decrease ingastric residue at 1.0 mg/kg and 2.5 mg/kg of RC-1139 showing adose-related acceleration of gastric emptying.

FIG. 2 is a bar graph of percentage of gastric emptying for rats withinduced post-operative gastric ileus administered saline or RC-1139 at adose of 1.01 mg/kg, 2.5 mg/kg or 10 mg/kg. The results demonstrate astatistically significant decrease in gastric residue at the 2.5 mg/kgdose and the 10 mg/kg dose.

FIG. 3 is a bar graph of percentage of gastric emptying for rats withinduced post-operative gastric ileus and morphine treatment (4 mg/kg),administered saline or RC-1139 at a dose of 2.5 mg/kg, 10 mg/kg or 50mg/kg. The results demonstrate a statistically significant decrease ingastric residue at the 10 mg/kg dose of RC-1139.

FIG. 4 is a bar graph of percentage of gastric emptying for rats withinduced post-operative gastric ileus and morphine treatment (12 mg/kg),administered saline or RC-1139 at a dose of 10 mg/kg. The results showthat at a 10 mg/kg dose, RC-1139 did not accelerate the delayed gastricemptying over the saline treated controls.

FIG. 5 is a bar graph of percentage of gastric emptying for normal ratswith morphine treatment (4 mg/kg) administered saline or RC-1139 at adose of 2.5 mg/kg or 10 mg/kg. The results demonstrate a statisticallysignificant decrease in gastric residue at the 2.5 mg/kg dose and the 10mg/kg dose of RC-1139.

FIG. 6 is a bar graph of percentage of gastric emptying for normal ratswith morphine treatment (12 mg/kg) administered saline or RC-1139 at adose of 2.5 mg/kg or 10 mg/kg: The results show a decrease(non-statistically significant) in gastric residue at the 2.5 mg/kg doseand the 10 mg/kg dose of RC-1139.

FIG. 7 is a bar graph of estimated effective doses of RC-1139 tostimulate gastric emptying in rats subjected to the experimentalconditions described herein.

The foregoing and other objects, features and advantages of theinvention will be apparent from the following more particulardescription of preferred embodiments of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method of stimulating the motility ofthe gastrointestinal system in a subject in need thereof, wherein thesubject suffers from maladies (i.e., disorders or diseases) of thegastrointestinal system. The method comprises administering to a subjectin need thereof a therapeutically effective amount of a growth hormonesecretagogue compound or a pharmaceutically acceptable salt, hydrate orsolvate thereof. In a particular embodiment, the growth hormonesecretagogue is a compound represented by any of Formulas I-XVI, or apharmaceutically acceptable salt, hydrate or solvate thereof.

In one embodiment, stimulation of gastrointestinal motility is used in amethod of treating opioid induced constipation in a subject in needthereof comprising administering a therapeutically effective amount of agrowth hormone secretagogue compound or a pharmaceutically acceptablesalt, hydrate or solvate thereof. In one embodiment, the subject isusing opioids for post-surgical pain management. In another embodiment,the subject is using opioids for chronic pain management. Suitableopioids include, but are not limited to, percocet, morphine, vicoden,methadone, oxycodone, and fentanyl. In a particular embodiment, thegrowth hormone secretagogue is a compound represented by any of FormulasI-XVI, or a pharmaceutically acceptable salt, hydrate or solvatethereof.

In another embodiment, stimulation of gastrointestinal motility is usedin a method of treating diabetes related gastroparesis in a subject inneed thereof comprising administering a therapeutically effective amountof a growth hormone secretagogue compound. In a particular embodiment,the growth hormone secretagogue is a compound represented by any ofFormulas I-XVI, or a pharmaceutically acceptable salt, hydrate orsolvate thereof.

In a further embodiment, stimulation of gastrointestinal motility isused in a method of treating gastroesophageal reflux disease (GERD) in asubject in need thereof comprising administering a therapeuticallyeffective amount of a growth hormone secretagogue compound. In aparticular embodiment, the growth hormone secretagogue is a compoundrepresented by any of Formulas I-XVI, or a pharmaceutically acceptablesalt, hydrate or solvate thereof is administered. In a particularembodiment, the gastroesophageal reflux disease is nocturnalgastroesophageal reflux disease.

In yet another embodiment, stimulation of gastrointestinal motility isused in a method of treating irritable bowel syndrome (IBS) in a subjectin need thereof comprising administering a therapeutically effectiveamount of a growth hormone secretagogue compound. In a particularembodiment, the growth hormone secretagogue is a compound represented byany of Formulas I-XVI, or a pharmaceutically acceptable salt, hydrate orsolvate thereof. In a particular embodiment, the irritable bowelsyndrome is constipation-predominant irritable bowel syndrome. In oneembodiment the irritable bowel syndrome is alternatingconstipation/diarrhea irritable bowel syndrome.

In one embodiment, stimulation of gastrointestinal motility is used in amethod of treating constipation in a subject in need thereof comprisingadministering a therapeutically effective amount of a growth hormonesecretagogue compound. In a particular embodiment, the growth hormonesecretagogue is a compound represented by any of Formulas I-XVI, or apharmaceutically acceptable salt, hydrate or solvate thereof.

In one embodiment, stimulation of gastrointestinal motility is used in amethod of treating post-operative ileus in a subject in need thereofcomprising administering a therapeutically effective amount of a growthhormone secretagogue compound. In a particular embodiment; the growthhormone secretagogue is represented by a compound represented by any ofFormulas I-XVI, or a pharmaceutically acceptable salt, hydrate orsolvate thereof.

Opioid Induced Constipation

Use of opioid analgesics to relieve chronic pain can cause effects onorgans outside the targets in the central nervous system. For example,the opioid action can slow stomach emptying and inhibit bowel movement.The increased time of fecal contents in the intestines results inexcessive absorption of water and sodium from fecal contents, resultingin harder, drier stools and constipation, afflicting approximately 90%of individuals on analgesic pain killers. For chronic pain patients onopioid medications, the resulting constipation can be a dose limitingside-effect. In addition, analgesics used for post-surgical painmanagement can cause opioid induced constipation. Suitable opioidsinclude, but are not limited to, percocet, morphine, vicoden, methadone,oxycodone and fentanyl, or any combination thereof.

In one embodiment, the method of treating opioid induced constipationcomprises co-administering a growth hormone secretagogue compound with atherapeutically effective amount of a peripherally acting opioidantagonist, a laxative, or any combination thereof. Suitableperipherally acting opioid antagonists include, but are not limited to,methylnaltrexone, naltrexone, nalmefene, naloxone and alvimopan or anycombination thereof. Suitable laxatives include, but are not limited tobulk forming laxatives, lubricant laxatives, stool softeners, or anycombination thereof.

Constipation

Constipation is a condition in which a person has uncomfortable orinfrequent bowel movements. A person with constipation produces hardstools that can be difficult to pass. The person also can feel as thoughthe rectum has not been completely emptied. Acute constipation beginssuddenly and noticeably. Chronic constipation, on the other hand, canbegin insidiously and persist for months or years.

The effectiveness of a candidate growth hormone secretagogue compound intreating constipation can be assessed, for example, using a ratcathartic colon model in which constipation is induced by feeding rats acontact laxative such as phenolphthalein or rhubarb (see, e.g., Liu etal., World J. Gastroenterol. 10:1672-1674 (2004)). After the inductionof cathartic colon, constipation is estimated as the number or weight offecal pellets per unit time (e.g., Nakamura et al., J. Nutr. Sci.Vitaminol. 47:367-372 (2001)) or using a gastrointestinal transit timeassay such as the charcoal meal test (Singh et al., Eur. J. Pharmacol.307:283-289 (1996)). Rats with cathartic colon show decreased fecaloutput or increased gastrointestinal transit time compared to controlrats. The administration of a growth hormone secretagogue compound whichis effective at treating constipation increases the number or weight offecal pellets or decreases gastrointestinal transit time in the ratcathartic colon model. An effective dose of growth hormone secretagoguefor treating constipation can be in the range of 0.1 to 100 mg/kg,preferably in the range of 1 to 20 mg/kg, and more preferably in therange of 2 to 10 mg/kg.

In one embodiment, the method of treating constipation comprisesco-administering a growth hormone secretagogue compound with atherapeutically effective amount of a laxative. Suitable laxativesinclude, but are not limited to, bulk forming laxatives, lubricantlaxatives, stool softeners, or any combination thereof.

Post-Operative Ileus

It is well established that the motility of the gastrointestinal (GI)tract is temporarily impaired after surgery. The effect that anabdominal operation has on gastrointestinal motility is generallyreferred to as “postoperative ileus,” a term denoting disruption of thenormal coordinated movements of the gut, resulting in failure of thepropulsion of intestinal contents. Ileus has also been defined as afunctional, nonmechanical obstruction of the bowel. The term“post-operative” ileus refers to delay in normal gastric and colonicemptying.

In one embodiment, the method of treating post-operative ileus comprisesco-administering a growth hormone secretagogue compound with atherapeutically effective amount of a dopamine antagonist. Suitabledopamine antagonists include, but are not limited to, bethanecol,metoclopramide, domperidone, amisulpride, clebopride, mosapramine,nemonapride, remoxipride, risperidone, sulpiride, sultopride andziprasidone, or any combination thereof.

Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a functional disorder effectingmotility of the entire gastrointestinal tract that can produce abdominalpain, constipation, and/or diarrhea. The impaired movement of thedigestive tract in IBS is not accompanied by a change in physicalstructure, such as inflammation or tumors. The symptoms of IBS arethought to be related to abnormal muscle contractions in any part of theintestines.

In this syndrome, the gastrointestinal tract is especially sensitive togastrointestinal stimuli. Stress, diet, drugs, hormones, or minorirritants can cause the gastrointestinal tract to contract abnormally.There are different types of IBS: constipation-predominant,diarrhea-predominant and alternatingconstipation-predominant/diarrhea-predominant IBS.

The effectiveness of a candidate growth hormone secretagogue compound intreating IBS can be assessed, for example, using a rat model in whichcolitis is induced in rats by intracolonic installation of 4% aceticacid (see, e.g., La et al., World J. Gastroenterol. 9:2791-2795 (2003)).After the colitis has subsided (e.g., about seven days after acetic acidtreatment), the rats are subjected to a restraint stress test, andstress-induced fecal output is measured. Rats that have undergonecolitis induction show increased stress-induced fecal output compared tocontrol rats. The administration of a growth hormone secretagoguecompound which is effective at treating IBS reduces the amount ofstress-induced defecation in the rat colitis model. An effective dose ofgrowth hormone secretagogue for treating IBS can be in the range of 0.1to 100 mg/kg, preferably in the range of 1 to 20 mg/kg, and morepreferably in the range of 2 to 10 mg/kg.

In one embodiment, the method of treating IBS comprises co-administeringa growth hormone secretagogue compound with a therapeutically effectiveamount of H₂ receptor antagonist; a serotonin 5-HT₄ agonist; a laxative;or any combination thereof.

Suitable H₂ receptor antagonists include, but are not limited to,nizatidine, ranitidine, famotidine, and cimetidine, rabeprazole, or anycombination thereof. Suitable 5-HT₄ receptor agonist include, but arenot limited to, sumatriptan, rauwolscine, yohimbine, metoclopramide,tegaserod, or any combination thereof. Suitable laxatives include, butare not limited to, bulk forming laxatives, lubricant laxatives, stoolsofteners, or any combination thereof.

Gastroesophageal Reflux Disorder

Gastroesophageal reflux disease (GERD) is a condition in which gastricstomach contents (e.g., bile salts) back up into the food pipe(esophagus), causing chronic regurgitation of gastric contents from thestomach into the lower esophagus. Commonly known as heartburn, GERDcauses esophageal irritation and inflammation.

For people with GERD, the esophageal sphincter (a ring-shaped musclelocated at the lower end of the esophagus to prevent stomach contentsfrom going backwards into the esophagus) can fail to carry out itsprotective duties. Instead of opening only when a person is eating orswallowing, it relaxes and allows digestive juices to reflux into theesophagus and irritate the esophageal lining.

Two types of GERD have been identified, upright or daytime GERD andsupine or nocturnal GERD. Nocturnal reflux episodes occur lessfrequently, but acid clearance is more prolonged. Nocturnal reflux canbe associated with the complications of GERD, such as esophagealerosions, ulceration, and respiratory symptoms. An estimated 17 millionAmericans currently suffer from heartburn and other symptoms of GERD.

The effectiveness of a candidate growth hormone secretagogue compound intreating GERD can be assessed, for example, using a rat model in whichGERD is induced in rats by a pyloric ligation surgical procedure (see,e.g., Tugay et al., 7. Surg. Res. 115:272-8 (2003)) in conjunction withthe rat gastric emptying assay described below (see “Study in a RatModel” under “Normal Conscious Rats”). The gastric emptying assay can beperformed after the rats have recovered from surgery. Sham operated ratscan be used as controls. Rats that have undergone pyloric ligation havehigher amounts of gastric radioactivity at the end of the assay comparedwith control rats. The administration of a growth hormone secretagoguecompound which is effective at treating GERD reduces the amount ofgastric radioactivity at the end of the assay. An effective dose ofgrowth hormone secretagogue for treating GERD can be in the range of 0.1to 100 mg/kg, preferably in the range of 1 to 20 mg/kg, and morepreferably in the range of 2 to 10 mg/kg.

In one embodiment, the method of treating GERD comprisesco-administering a growth hormone secretagogue compound with atherapeutically effective amount of H₂ receptor antagonist; an antacid;a proton pump inhibitor; or any combination thereof.

The effectiveness of a candidate growth hormone secretagogue compound intreating gastroparesis, including diabetes-induced gastroparesis, can beassessed, for example, using the rat gastric emptying assay describedbelow (see “Study in a Rat Model” under “Normal Conscious Rats”). Ratswith diabetes induced using streptozotocin are compared to controls.See, e.g., Rees et al., Diabet. Med. 22:359-70 (2005) for a discussionof various rat models of diabetes. Rats showing diabetes-inducedgastroparesis have higher amounts of gastric radioactivity at the end ofthe assay compared with normal control rats. The administration of agrowth hormone secretagogue compound which is effective at treatingdiabetes-induced gastroparesis reduces the amount of gastricradioactivity at the end of the assay. An effective dose of growthhormone secretagogue for treating diabetes-induced gastroparesis can bein the range of 0.1 to 100 mg/kg, preferably in the range of Ito 20mg/kg, and more preferably in the range of 2 to 10 mg/kg. The diabeticrat gastric motility assay can be used to determine an optimum effectivedose for a given candidate compound.

Suitable H₂ receptor antagonist include, but are not limited to,nizatidine, ranitidine, famotidine, and cimetidine, rabeprazole, or anycombination thereof. Suitable antacids include, but are not limited to,aluminum and magnesium hydroxide and combinations thereof. Suitableproton pump inhibitors include, but are not limited to, esomeprazole(NEXIUM®), omeprazole, lansoprazole, pantoprazole, or a combinationthereof.

Diabetes Related Gastroparesis

Gastroparesis, also referred to as delayed gastric emptying, is adisorder in which the stomach takes too long to empty its contents. Itoften occurs in people with type 1 diabetes or type 2 diabetes.Gastroparesis can occur when nerves to the stomach are damaged or stopworking. The vagus nerve controls the movement of food through thedigestive tract. If the vagus nerve is damaged, the muscles of thestomach and intestines do not work normally, and the movement of food isslowed or stopped. Diabetes can damage the vagus nerve if blood glucoselevels remain high over a long period of time. High blood glucose causeschemical changes in nerves and damages the blood vessels that carryoxygen and nutrients to the nerves.

The effectiveness of a candidate growth hormone secretagogue compound intreating gastroparesis, including diabetes-induced gastroparesis, can beassessed, for example, using the rat gastric emptying assay describedbelow (see “Study in a Rat Model” under “Normal Conscious Rats”). Ratswith diabetes induced using streptozotocin are compared to controls.See, e.g., Rees et al., Diabet. Med. 22:359-70 (2005) for a discussionof various rat models of diabetes. Rats showing diabetes-inducedgastroparesis have higher amounts of gastric radioactivity at the end ofthe assay compared with normal control rats. The administration of agrowth hormone secretagogue compound which is effective at treatingdiabetes-induced gastroparesis reduces the amount of gastricradioactivity at the end of the assay. An effective dose of growthhormone secretagogue for treating diabetes-induced gastroparesis can bein the range of 0.1 to 100 mg/kg, preferably in the range of 1 to 20mg/kg, and more preferably in the range of 2 to 10 mg/kg.

In one embodiment, the method of treating diabetes related gastroparesiscomprises co-administering a growth hormone secretagogue compound with atherapeutically effective amount of dopamine antagonist. Suitabledopamine antagonists include, but are not limited to, bethanecol,metoclopramide, domperidone, amisulpride, clebopride, mosapramine,nemonapride, remoxipride, risperidone, sulpiride, sultopride andziprasidone, or any combination thereof.

The invention further relates to pharmaceutical compositions useful forstimulating (i.e., inducing) motility of the gastrointestinal system.The pharmaceutical composition comprises a growth hormone secretagogueand optionally a pharmaceutically acceptable carrier. The pharmaceuticalcomposition can comprise a second amount of a suitable therapeuticagent. A suitable therapeutic agent can be determined based on thecondition being treated in the subject.

For example, the pharmaceutical composition can comprise a first amountof a growth hormone secretagogue and a second amount of a laxative whentreating constipation: The pharmaceutical composition of the presentinvention can optionally contain a pharmaceutically acceptable carrier.The growth hormone secretagogue and laxative can each be present in thepharmaceutical composition in a therapeutically effective amount. Inanother aspect, said first and second amount can together comprise atherapeutically effective amount.

In a particular embodiment, the pharmaceutical composition can comprisea first amount of a growth hormone secretagogue and a second amount of aH₂ receptor antagonist. The pharmaceutical composition of the presentinvention can optionally contain a pharmaceutically acceptable carrier.The growth hormone secretagogue and H₂ receptor antagonist can each bepresent in the pharmaceutical composition in a therapeutically effectiveamount. In another aspect, said first and second amount can togethercomprise a therapeutically effective amount.

In another embodiment, the pharmaceutical composition can comprise afirst amount of a growth hormone secretagogue and a second amount of aserotonin 5-HT₄ agonist. The pharmaceutical composition of the presentinvention can optionally contain a pharmaceutically acceptable carrier.The growth hormone secretagogue and serotonin 5-HT₄ agonist can each bepresent in the pharmaceutical composition in a therapeutically effectiveamount. In another aspect, said first and second amount can togethercomprise a therapeutically effective amount.

In yet another embodiment, the pharmaceutical composition can comprise afirst amount of a growth hormone secretagogue and a second amount of anantacid. The pharmaceutical composition of the present invention canoptionally contain a pharmaceutically acceptable carrier. The growthhormone secretagogue and antacid can each be present in thepharmaceutical composition in a therapeutically effective amount. Inanother aspect, said first and second amount can together comprise atherapeutically effective amount.

In a particular embodiment, the pharmaceutical composition can comprisea first amount of a growth hormone secretagogue and a second amount ofan opioid antagonist. The pharmaceutical composition of the presentinvention can optionally contain a pharmaceutically acceptable carrier.The growth hormone secretagogue and opioid antagonist can each bepresent in the pharmaceutical composition in a therapeutically effectiveamount. In another aspect, said first and second amount can togethercomprise a therapeutically effective amount.

In another embodiment, the pharmaceutical composition can comprise afirst amount of a growth hormone secretagogue and a second amount of aproton pump inhibitor. The pharmaceutical composition of the presentinvention can optionally contain a pharmaceutically acceptable carrier.The growth hormone secretagogue and proton pump inhibitor can each bepresent in the pharmaceutical composition in a therapeutically effectiveamount. In another aspect, said first and second amount can togethercomprise a therapeutically effective amount.

In another embodiment, the pharmaceutical composition can comprise afirst amount of a growth hormone secretagogue and a second amount of amotilin receptor agonist. The pharmaceutical composition of the presentinvention can optionally contain a pharmaceutically acceptable carrier.The growth hormone secretagogue and motilin receptor agonist can each bepresent in the pharmaceutical composition in a therapeutically effectiveamount. In another aspect, said first and second amount can togethercomprise a therapeutically effective amount.

In another embodiment, the pharmaceutical composition can comprise afirst amount of a growth hormone secretagogue and a second amount of adopamine antagonist. The pharmaceutical composition of the presentinvention can optionally contain a pharmaceutically acceptable carrier.The growth hormone secretagogue and dopamine antagonist can each bepresent in the pharmaceutical composition in a therapeutically effectiveamount. In another aspect, said first and second amount can togethercomprise a therapeutically effective amount.

In another embodiment, the pharmaceutical composition can comprise afirst amount of a growth hormone secretagogue and a second amount of acholinesterase inhibitor. The pharmaceutical composition of the presentinvention can optionally contain a pharmaceutically acceptable carrier.The growth hormone secretagogue and cholinesterase inhibitor can each bepresent in the pharmaceutical composition in a therapeutically effectiveamount. In another aspect, said first and second amount can togethercomprise a therapeutically effective amount.

In another embodiment, the pharmaceutical composition can comprise afirst amount of a growth hormone secretagogue and a second amount ofsomatostatin. The pharmaceutical composition of the present inventioncan optionally contain a pharmaceutically acceptable carrier. The growthhormone secretagogue and somatostatin can each be present in thepharmaceutical composition in a therapeutically effective amount. Inanother aspect, said first and second amount can together comprise atherapeutically effective amount.

In another embodiment, the pharmaceutical composition can comprise afirst amount of a growth hormone secretagogue and a second amount ofoctreotide. The pharmaceutical composition of the present invention canoptionally contain a pharmaceutically acceptable carrier. The growthhormone secretagogue and octreotide can each be present in thepharmaceutical composition in a therapeutically effective amount. Inanother aspect, said first and second amount can together comprise atherapeutically effective amount.

The invention further relates to use of a growth hormone secretagoguecompound for the manufacture of a medicament for stimulating (i.e.,inducing) the motility of the gastrointestinal system.

Growth Hormone Secretagogues/Ghrelin Agonists

As used herein, the terms growth hormone secretagogue compound andghrelin agonist are synonymous. A growth hormone secretagogue or ghrelinagonist therefore refers to a substance (e.g., a molecule, a compound)which promotes (induces or enhances) at least one functioncharacteristic of a growth hormone secretagogue receptor (GHS receptor)also referred to in the art as a ghrelin receptor. In one embodiment,the growth hormone secretagogue compound or ghrelin agonist binds theGHS receptor or ghrelin receptor (i.e., is a ghrelin or GHS receptoragonist) and induces the secretion of growth hormone. A compound havingGHS receptor agonist activity (e.g., a GHS receptor or ghrelin receptoragonist) can be identified and activity assessed by any suitable method.For example, the binding affinity of a GHS receptor agonist to the GHSreceptor can be determined employing receptor binding assays and growthhormone stimulation can be assessed as described in PublishedInternational Application No. WO 00/01726, incorporated herein byreference.

GHS receptors and ghrelin receptors are expressed in the hypothalamus,pituitary and pancreas, among other tissues. Activation of thesereceptors in the pituitary induces the secretion of growth hormone. Inaddition to inducing the secretion of growth hormone, recent studieshave shown the growth hormone secretagogues can increase appetite andbody weight. At typical doses, growth hormone secretagogues are alsoknown to induce the secretion of IGF-1. In a particular embodiment, thegrowth hormone secretagogue compounds are those described in U.S. Pat.Nos. 6,303,620, 6,576,648, 5,977,178, 6,566,337, 6,083,908, 6,274,584and Published International Application No. WO 00/01726, the entirecontent of all of which are incorporated herein by reference.

In a particular embodiment, the growth hormone secretagogue isrepresented by the structural Formula I:

wherein:

R¹ is hydrogen, or C₁₋₆-alkyl optionally substituted with one or morearyl or hetaryl;

a and d are independently 0, 1, 2 or 3;

b and c are independently 0, 1, 2, 3, 4 or 5, provided that b+c is 3, 4or 5;

D is R²—NH—(CR³R⁴)_(e)—(CH₂)_(f)-M-(CHR⁵)_(g)—(CH₂)_(h)—

wherein:

R², R³, R⁴ and R⁵ are independently hydrogen or C₁₋₆ alkyl optionallysubstituted with one or more halogen, amino, hydroxyl, aryl or hetaryl;or

R² and R³ or R² and R⁴ or R³ and R⁴ can optionally form—(CH₂)_(i)—U—(CH₂)_(j)—, wherein i and j are independently 1 or 2 and Uis —O—, S— or a valence bond;

h and f are independently 0, 1, 2, or 3;

g and e are independently 0 or 1;

M is a valence bond, —CR⁶══CR⁷—, arylene, hetarylene, —O— or —S—;

R⁶ and R⁷ are independently hydrogen, or C₁₋₆-alkyl optionallysubstituted with one or more aryl or hetaryl;

G is —O—(CH₂)_(k)—R⁸,

J is —O—(CH₂)_(i)—R¹³,

wherein:

R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ independently arehydrogen, halogen, aryl, hetaryl, C₁₋₆-alkyl or C₁₋₆-alkoxy;

k and l are independently 0, 1 or 2;

E is —CONR¹⁸R¹⁹, —COOR¹⁹, —(CH₂)_(m)—NR¹⁸SO₂R²⁰, —(CH₂)_(m),—NR¹⁸—COR²⁰, —(CH₂)_(m)—OR¹⁹, —(CH₂)_(m)—OCOR²⁰, —CH(R¹⁸)R¹⁹,—(CH₂)_(m)—NR¹⁸—CS—NR¹⁹R²¹ or —(CH₂)_(m)—NR¹⁸—CO—NR¹⁹R²¹; or

E is —CONR²²NR²³R²⁴, wherein R²² is hydrogen, C₁₋₆-alkyl optionallysubstituted with one or more aryl or hetaryl, or aryl or hetaryloptionally substituted with one or more C₁₋₆-alkyl; R²³ is C₁₋₆-alkyloptionally substituted with one or more aryl or hetaryl, or C₁₋₇-acyl;and R²⁴ is hydrogen, C₁₋₆-alkyl optionally substituted with one or morearyl or hetaryl; or aryl or hetaryl optionally substituted with one ormore C₁₋₆-alkyl; or

R²² and R²³ together with the nitrogen atoms to which they are attachedcan form a heterocyclic system optionally substituted with one or moreC₁₋₆-alkyl, halogen, amino, hydroxyl, aryl or hetaryl; or

R²² and R²⁴ together with the nitrogen atoms to which they are attachedcan form a heterocyclic system optionally substituted with one or moreC₁₋₆-alkyl, halogen, amino, hydroxyl, aryl or hetaryl; or

R²³ and R²⁴ together with the nitrogen atom to which they are attachedcan form a heterocyclic system optionally substituted with one or moreC₁₋₆-alkyl, halogen, amino, hydroxyl, aryl or hetaryl;

wherein m is 0, 1, 2 or 3,

R¹⁸, R¹⁹ and R²¹ independently are hydrogen or C₁₋₆-alkyl optionallysubstituted with halogen, —N(R²⁵)R²⁶, wherein R²⁵ and R²⁶ areindependently hydrogen or C₁₋₆ alkyl; hydroxyl, C₁₋₆-alkoxy,C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylcarbonyloxy or aryl; or R¹⁹ is

wherein

Q is —CH< or —N<,

K and L are independently —CH₂—, —CO—, —O—, —S—, —NR²⁷— or a valencebond, where R²⁷ is hydrogen or C₁₋₆ alkyl; .

n and o are independently 0, 1, 2, 3 or 4;

R²⁰ is C₁₋₆ alkyl, aryl or hetaryl;

or a pharmaceutically acceptable salt thereof;with the proviso that if M is a valence bond then E is —CONR²²NR²³R²⁴.

In another embodiment, R¹ is C₁₋₆-alkyl. In yet another embodiment, a is1.

In one embodiment, d is 1. In another embodiment, b+c is 4.

In yet another embodiment, D is

R²—NH —(CR³R⁴)_(e)—(CH₂)_(f)-M-(CHR⁵)_(g)—(CH₂)_(h)—

wherein

R², R³, R⁴ and R⁵ are independently hydrogen or C₁₋₆ alkyl optionallysubstituted with a halogen, amino, hydroxyl, aryl or hetaryl; or

R² and R³ or R² and R⁴ or R³ and R⁴ can optionally form—(CH₂)_(i)—U—(CH₂)_(j)—, wherein i and j are independently 1 or 2 and Uis —O—, —S— or a valence bond;

h and f are independently 0, 1, 2, or 3;

g and e are independently 0 or 1;

M is —CR⁶═CR⁷—, arylene, hetarylene, —O— or —S—; and

R⁶ and R⁷ are independently hydrogen, or C₁₋₆-alkyl.

In a further embodiment, D is

R²—NH—(CR³R⁴)_(e)—(CH₂)_(f)-M-(CHR⁵)_(g)—(CH₂)_(h)—

wherein:

R², R³, R⁴ and R⁵ are independently hydrogen or C₁₋₆ alkyl optionallysubstituted with a halogen, amino, hydroxyl, aryl or hetaryl; or

R² and R³ or R² and R⁴ or R³ and R⁴ can optionally form—(CH₂)_(i)—U—(CH₂)_(j)—, wherein i and j are independently 1 or 2 and Uis —O—, —S— or a valence bond;h and f are independently 0, 1, 2, or 3; g and e are independently 0 or1; M is a valence bond.

In another embodiment, G is

wherein:

R⁸, R⁹, R¹⁰, R¹¹ and R¹² independently are hydrogen, halogen, aryl,hetaryl, C₁₋₆-alkyl or C₁₋₆ alkoxy; and k is 0, or 2.

In yet another embodiment, J is

wherein:

R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ independently are hydrogen, halogen, aryl,hetaryl, C₁₋₆-alkyl or C₁₋₆-alkoxy.

In one embodiment, E is —CONR¹⁸R¹⁹, —COOR¹⁹ or —(CH₂)—, —OR¹⁹,

wherein:

m is 0, 1, 2 or 3;

R¹⁸ and R¹⁹ independently are hydrogen or C₁₋₆-alkyl optionallysubstituted by halogen, —N(R²⁵)R²⁶ wherein R²⁵ and R²⁶ are independentlyhydrogen or C₁₋₆ alkyl; hydroxyl, C₁₋₆-alkoxy, C₁₋₆-alkoxycarbonyl,C₁₋₆-alkylcarbonyloxy or aryl.

In another embodiment, E is —CONR²²NR²³R²⁴

wherein:

R²² is hydrogen, C₁₋₆-alkyl optionally substituted with an aryl orhetaryl, or aryl or hetaryl optionally substituted with a C₁₋₆-alkyl;

R²³ is C₁₋₆-alkyl optionally substituted with one or more aryl orhetaryl, or C₁₋₇-acyl; and

R²⁴ is hydrogen, C₁₋₆-alkyl optionally substituted with an aryl orhetaryl; or aryl or hetaryl optionally substituted with a C₁₋₆-alkyl; or

R²² and R²³ together with the nitrogen atoms to which they are attachedcan form a heterocyclic system optionally substituted with a C₁₋₆-alkyl,halogen, amino, hydroxyl, aryl or hetaryl; or R²² and R²⁴ together withthe nitrogen atoms to which they are attached can form a heterocyclicsystem optionally substituted with a C₁₋₆-alkyl, halogen, amino,hydroxyl, aryl or hetaryl; or

R²³ and R²⁴ together with the nitrogen atom to which they are attachedcan form a heterocyclic system optionally substituted with a C₁₋₆-alkyl,halogen, amino, hydroxyl, aryl or hetaryl.

In a specific embodiment, the growth hormone secretagogue is representedby the structural Formula

In a preferred embodiment, the compound of Formula II has the (R)configuration at the chiral carbon designated by the asterisk (*) inFormula II. The chemical name of the compound of Formula II having the(R) configuration at the designated chiral carbon is:2-Amino-N-{(1R)-2-[3-benzyl-3-(N,N′,N′-trimethylhydrazinocarbonyl)piperidin-1-yl]-1-((1H-indol-3-yl)-2-oxoethyl}-2-methylpropionamide.Represented by structural Formula III:

and pharmaceutically acceptable salts thereof.

In a specific embodiment, the growth hormone secretagogue is representedby the structural Formula IV:

wherein

R¹ is hydrogen or C₁₋₆-alkyl;

R² is hydrogen or C₁₋₆-alkyl;

L is

wherein

R⁴ is hydrogen or C₁₋₆ alkyl;

p is 0 or 1;

q, s, t, u are independently 0, 1, 2, 3, or 4;

r is 1;

the sum q+r+s+t+u is 0, 1, 2, 3, or 4;

R⁹, R¹⁰, R¹¹, and R¹² are independently hydrogen or C₁₋₆ alkyl;

Q is >N—R¹³ or

wherein:

o is 0, 1 or 2;

T is —N(R¹⁵)(R¹⁶) or hydroxyl;

R¹³, R¹⁵, and R¹⁶ are independently hydrogen or C₁₋₆ alkyl;

R¹⁴ is hydrogen, aryl or hetaryl;

Or L is

wherein

p is 0 or 1;

q, s, t, u are independently 0, 1, 2, 3, or 4;

r is 0 or 1;

the sum q+r+s+t+u is 0, 1, 2, 3, or 4;

R⁹, R¹⁰, R¹¹, and R¹² are independently hydrogen or C₁₋₆ alkyl;

Q is >N—R¹³ or

wherein

o is 0, 1, or 2;

T is —N(R¹⁵)(R¹⁶) or hydroxyl;

R¹³, R¹⁵, and R¹⁶ are independently from each other hydrogen or C₁₋₆alkyl;

R¹⁴ is hydrogen, aryl, or hetaryl;

G is —O—O—(CH₂)—R¹⁷,

wherein:

R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ independently are hydrogen, halogen, aryl,hetaryl, C₁₋₆-alkyl or C₁₋₆-alkoxy;

K is 0, 1 or

J is —O—O(CH₂)_(l)—R²²,

wherein:

R²², R²³, R²⁴, R²⁵, and R²⁶ independently are hydrogen, halogen, aryl,hetaryl, C₁₋₆-alkyl or C₁₋₆-alkoxy;

l is 0, 1 or 2;

a is 0, 1, or 2;

b is 0, 1, or 2;

c is 0, 1, or 2;

d is 0 or 1;

e is 0, 1, 2, or 3;

f is 0 or 1;

R⁵ is hydrogen or C₁₋₆-alkyl optionally substituted with one or morehydroxyl, aryl or hetaryl;

R⁶ and R⁷ are independently hydrogen or C₁₋₆-alkyl, optionallysubstituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;

R⁸ is hydrogen or C₁₋₆-alkyl, optionally substituted with one or morehalogen, amino, hydroxyl, aryl, or hetaryl;

R⁶ and R⁷ or R⁶ and R⁸ or R⁷ and R⁸ can optionally form—(CH₂)_(i)—U—(CH₂)_(j)—, wherein i and j independently are 1, 2 or 3 andU is —O—, —S—, or a valence bond;

M is arylene, hetarylene, —O—, —S— or —CR²⁷═CR²⁸—;

R²⁷ and R²⁸ are independently hydrogen or C₁₋₆alkyl, optionallysubstituted with one or more aryl or hetaryl;

or a pharmaceutically acceptable salt thereof.

In another embodiment, R¹ is C₁₋₆-alkyl.

In yet another embodiment, R² is C₁₋₆-alkyl.

In one embodiment, L is

wherein R⁴ is hydrogen or C₁₋₆ alkyl;p is 0 or 1;q, s, t, u are independently from each other 0, 1, 2, 3 or 4;r is 0 or 1;the sum q+r+s+t+u is 0, 1, 2, 3, or 4;R⁹, R¹⁰, R¹¹, and R¹² are independently from each other hydrogen or C₁₋₆alkyl;

Q is >N—R¹³ or

wherein:

o is 0, 1 or 2;

T is —N(R¹⁵)(R¹⁶) or hydroxyl;

R¹³, R¹⁵, and R¹⁶ are independently from each other hydrogen or C₁₋₆alkyl; and

R¹⁴ is hydrogen, aryl or hetaryl.

In another embodiment, L is

wherein:

q, s, t, u are independently from each other 0, 1, 2, 3 or 4;

r is 0 or 1;

the sum q+r+s+t+u is 0, 1, 2, 3, or 4;

R⁹, R¹⁰, R¹¹, and R¹² are independently from each other hydrogen or C₁₋₆alkyl;

Q is >N—R¹³ or

wherein:

o is 0, 1 or 2;

T is —N(R¹⁵)(R¹⁶) or hydroxyl;

R¹³, R¹⁵, and R¹⁶ are independently from each other hydrogen or C₁₋₆alkyl; and

R¹⁴ is hydrogen, aryl or hetaryl.

In yet another embodiment, G is

wherein:

R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ independently from each other are hydrogen;halogen, aryl, hetaryl, C₁₋₆-alkyl or C₁₋₆-alkoxy.

In one embodiment, J is

wherein:

R²², R²³, R²⁴, R²⁵ and R²⁶ independently from each other are hydrogen,halogen, aryl, hetaryl, C₁₋₆-alkyl or C₁₋₆-alkoxy.

In another embodiment, M is arylene or —CR²⁷═CR²⁸—, wherein R²⁷ and R²⁸independently from each other hydrogen or C₁₋₆-alkyl, optionallysubstituted with aryl or hetaryl.

In yet another embodiment, R⁶ and R⁷ independently from each other arehydrogen or C₁₋₆-alkyl.

In yet another embodiment, R⁶ and R⁷ form —(CH₂)_(i)—U—(CH₂)_(j)—,wherein i and j independently from each other are 1, 2 or 3 and U is—O—, —S—, or a valence bond.

In one embodiment, R⁸ is hydrogen or C₁₋₆-alkyl.

In another embodiment, the growth hormone secretagogue compound isrepresented by the structural Formula V. The chemical name of thecompound of Formula V is (2E)-5-Amino-5-methylhex-2-enoic acidN-((1R)-1-{N-[(1R)-1-benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(biphenyl-4-yl)ethyl)-N-methylamide,also referred to herein as RC-1139. The RC-1139 is represented bystructural Formula V:

and pharmaceutically acceptable salts thereof.

Other compounds of interest include the following:

-   1-{(2R)-2-[N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino]-3-(2-naphthyl)propionyl}-4-benzylpiperidine-4-carboxylic    acid methylamide,

-   1-{(1R)-2-[N-((2E)-5-Amino-3,5-dimethylhex-2-enoyl)-N-methylamino]-3-(2-naphthyl)propionyl}-4-benzylpiperidine-4-carboxylic    acid methylamide

-   1-{(2R)-2-[N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino]-3-(biphenyl-4-yl)propionyl}4-benzylpiperidine-4-carboxylic    acid methylamide

-   1-{(2R)-2-[N-((2E)-5-Amino-3,5-dimethylhex-2-enoyl)-N-methylamino]-3-(biphenyl-4-yl)propionyl}-4-benzylpiperidine-4-carboxylic    acid methylamide

-   1-((2R)-2-{N-[(2E)4-(1-Aminocyclobutyl)but-2-enoyl]-N-methylamino}-3-(biphenyl-4-yl)propionyl)4-benzylpiperidine-4-carboxylic    acid methylamide

-   2-Amino-N-[(1R)-2-[4-benzyl-4-(N′,N′-dimethylhydrazinocarbonyl)piperidin-1-yl]-1-((1H-indol-3-yl)methyl)-2-oxoethyl]-2-methylpropionamide

-   2-Amino-N-{(1R)-2-[(3R)-3-benzyl-3-(N′,N′-dimethyl-hydrazinocarbonyl)-piperidin-1-yl]-1-benzyloxymethyl-2-oxo-ethyl}-2-methyl-propionamide

-   2-Amino-N-[(1R)-2-[(3R)-3-benzyl-3-(N′N′-dimethylhydrazinocarbonyl)-piperidin-1-yl]-1-((1H-indol-3-yl)methyl)-2-oxoethyl]-2-methylpropionamide

-   1-{(2R)-2-[N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino]-3-(biphenyl-4-yl)propionyl}-4-benzylpiperidine-4-carboxylic    acid ethyl ester

-   1-{(2R)-2-[N-((2E)-5-Amino-3,5-dimethylhex-2-enoyl)-N-methylamino]-3-(biphenyl-4-yl)propionyl}-4-benzylpiperidine-4-carboxylic    acid ethyl ester

-   1-{(2R)-2-[N-((2E)-5-Amino-3,5-dimethylhex-2-enoyl)-N-methylamino]-3-(2-naphthyl)propionyl}-4-benzylpiperidine-4-carboxylic    acid ethyl ester

-   1-{(2R)-2-[N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino]-3-—(2-naphthyl)propionyl}-4-benzylpiperidine-4-carboxylic    acid ethyl ester

-   (3S)-1-[(2R)-((2E)-5-Amino-5-methylhex-2-enoylamino)-3-(1H-indol-3-yl)propionyl]-3-benzylpiperidine-3-carboxylic    acid ethyl ester

-   (3S)-1-[(2R)-2-((2E)-5-Amino-3,5-dimethylhex-2-enoylamino)-3-(1H-indol-3-yl)propionyl]-3-benzylpiperidine-3-carboxylic    acid ethyl ester

-   (3S)-1-[(2R)-2-(3-(Aminomethyl)benzoylamino)-3-(1H-indol-3-yl)propionyl]-3-benzylpiperidine-3-carboxylic    acid ethyl ester

-   (2E)-5-Amino-5-methylhex-2-enoic acid N-{(1R)-2-[4-benzyl-4    (N′,N′-dimethyl-hydrazinocarbonyl)piperidin-1-yl]-1-((2-naphthyl)methyl)-2-oxoethyl}-N-methylamide

-   (2E)-5-Amino-5-methylhex-2-enoic acid    N-[(1R)-2-[3-benzyl-3-(N′,N′-dimethyl-hydrazinocarbonyl)-piperidin-1-yl]-1-((1H-indol-3-yl)methyl)-2-oxoethyl]amide

-   (2E)-5-Amino-5-methylhex-2-enoic acid    N-{(1R)-2-[3-benzyl-3-(N′,N′-dimethyl-hydrazinocarbonyl)-piperidin-1-yl]-1-((2-naphthyl)methyl)-2-oxoethyl}-N-methyl-amide

-   2E)-5-Amino-5-methylhex-2-enoic acid {(1R)-2-[3-benz    yl-3-hydrazinocarbonyl)piperidin-1-yl]-1-(benzyloxymethyl)-2-oxoethyl}amide

-   2-Amino-N-{2-[3-benzyl-3-(N′,N′-dimethylhydrazinocarbonyl)piperidin-1-yl]-1-((2-naphthyl)methyl)-2-oxo-ethyl}-2-methyl-propionamide

-   2-Amino-N-{(1R)-2-[3-benzyl-3-(N′,N′-dimethylhydrazinocarbonyl)piperidin-1-yl]-1-((biphenyl-4-yl)methyl)-2-oxoethyl}-2-methylpropionamide

-   2-Amino-N-{(1R)-2-[3-benzyl-3-(N′,N′-dimethylhydrazinocarbonyl)piperidin-1-yl]-1-((1H-indol-3-yl)methyl)-2-oxoethyl}-2-methylpropionamide

-   2-Amino-N-{2-[3-benzyl-3-(N′-dimethylhydrazinocarbonyl)piperidin-1-yl]-1-(benzyloxymethyl)-2-oxoethyl}-2-methylpropionamide

-   2-Amino-N-{(1R-2-[3-benzyl-3-(N′,N′-dimethylhydrazinocarbonyl)piperidin-1-yl]-1-(benzyloxymethyl)-2-oxoethyl}-2-methylpropionamide

-   1-[(2R)-2-(2-Amino-2-methylpropionylamino)-3-(1-H-indol-3-yl)propionyl]-3-benzylpiperidine-3-carboxylic    acid (pyrrolidin-1-yl)amide

-   (2E)-5-Amino-5-Methylhex-2-enoic acid    N-((1R)-1-{N-[(1R)-1-benzyl-2-(4-((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide

-   (2E)-5-Amino-5-Methylhex-2-enoic acid N-((1R)-1    {N-[(1R)-1-benzyl-2-(3S)-3-(dimethylaminomethyl)piperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide

-   (2E)-4-(1-Aminocyclobutyl)but-2-enoic acid    N-((1R)-1-{N-[(1R)-1-benzyl-2-((3S)-3-(dimethylaminomethyl)piperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide

-   (2E)-5-Amino-5-methylhex-2-enoic acid    N-((1R)-1-{N-[(1R)-1-benzyl-2-((2S)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide

-   N-((1R)-1-{N-[1R)-1-Benzyl-2-(2S)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methyl-3-((methylamino)methyl)benzamide

-   (2E)-5-Amino-5-methylhex-2 enoic acid    N-((1R-1-{N-[(1R)-1-benzyl-2-(4-(dimethylamino)piperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide.

-   (2E)-5-Amino-5-methylhex-2-enoic acid    N-methyl-N-[(1R)-1-(N-methyl-N-{(1R)-1-[N-methyl-N-(1-methylpiperidin-4-yl)carbamoyl]-2-phenylethyl}carbamoyl)-2-(2-naphthyl)ethyl]amide

-   3-Aminomethyl-N-((1R)-1-{N-[1R)-1-benzyl-2-(4-methylpiperazin-1-yl)-2-oxoethyl]-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylbenzamide

-   (2E)-5-Amino-5-methylhex-2-enoic acid    N-((1R)-1-{N-[(1R)-1-benzyl-2-(4-methylpiperazin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)-N-methylamide

-   (2E)-5-Amino-5-methylhex-2-enoic acid    N-methyl-N-((1R)-1-{N-methyl-N-[(1R)-2-phenyl-1-((2,2,6,6-tetramethylpiperidin-4-yl)carbamoyl)ethyl]carbamoyl}-2-(2-naphthyl)ethyl)amide

-   3-Aminomethyl-N-methyl-N-((1R)1-{N-methyl-N-[(1R)-2-phenyl-1-((2,2,6,6-tetramethylpiperidin-4-yl)carbamoyl)ethyl]carbamoyl}-2-(2-naphthyl)ethyl)benzamide

-   (2E)-5-Amino-3,5-dimethylhex-2-enoic acid    N-methyl-N-((1R-1-{N-methyl-N-[(1R)-2-phenyl-1-((2,2,6,6-tetramethylpiperidin-4-yl)carbamoyl)ethyl]carbamoyl}-2-(2-naphthyl)ethyl)amide

-   (2E)-4-(1-Aminocyclobutyl)but-2-enoic acid    N-((1R)1-{N-([1R)1-benzyl-2-(4-methylpiperazin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide

-   (2E)-5-Amino-3,5-dimethylhex-2-enoic acid    N-((1R)1-{N-[(1R)1-benzyl-2-(4-methylpiperazin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide

-   (2E)-4-(1-Aminocyclobutyl)but-2-enoic acid    N-((1R)-1-{N-[(1R)-1-benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(biphenyl-4-yl)ethyl)-N-methylamide

-   (2E)-5-Amino-3,5-dimethylhex-2enoic acid    N-((1R)-1-{N-[(1R)-1-benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(biphenyl-4-yl)ethyl)-N-methylamide

-   (2E)-5-Amino-5-methylhex-2-enoic acid    N-((1R)-1-{N-[(1R)-1-benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide

-   (2E)-5-Amino-3,5-dimethylhex-2-enoic acid    N-((1R)-1-{N-[(1R)-1-benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide

-   (2E)-4-(1-Aminocyclobutyl)but-2-enoic acid    N-((1R)-1-{N-[(1R)-1-benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide

-   (2E)-5-Amino-5-methylhex-2-enoic acid    N-((1R)-1-{N-[(1R)-1-(4-fluorobenzyl)-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide

-   (2E)-5-Amino-3,5-dimethylhex-2-enoic acid    N-((1R)-1-{N-[(1R)-1-(4-fluorobenzyl)-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide

-   (2E)-5-Amino-5-methylhex-2-enoic acid    N-((1R)-1-{N-[(1R)-1-benzyl-2-(4-hydroxy-4-(2-thienyl)piperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide

-   (2E)-5-Amino-5-methylhex-2-enoic acid    N-((1R)-1-{N-[(1R)-1-(3-hydroxycyclohexylcarbamoyl)-2-phenylethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide

-   (2E)4-(1-Aminocyclobutyl)but-2-enoic acid    N-((1R)-1-{N-[(1R)-1-benzyl-2-(4-(dimethylamino)piperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide

-   (2E)-5-Amino-5-methylhex-2-enoic acid    N-((1R)-1-{N-[(2R)-2-(4-hydroxypiperidin-1-yl)-2-oxo-1((2-thienyl)methyl)ethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide

-   (2E)-5-Amino-3,5-dimethylhex-2-enoic acid    N-((1R)-1-{N-[2R)-2-(4-hydroxypiperidin-1-yl)-2-oxo-1-((2-thienyl)methyl)ethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide

-   (2E)-5-Amino-5-methylhex-2-enoic acid    N-((1R)-2-(biphenyl-4-yl)-1-{N-[(2R)-2-(4-hydroxypiperidin-1-yl)-2-oxo-1-((2-thienyl)methyl)ethyl]-N-methylcarbamoyl}ethyl)-N-methylamide

-   (2E)-5-Amino-3,5-dimethylhex-2-enoic acid    N-((1R)-2-(biphenyl-4-yl)-1-{N-[(1R)-2-(4-hydroxypiperidin-1-yl)-2-oxo-1-((2-thienyl)methyl)ethyl]-N-methylcarbamoyl}ethyl)-N-methylamide

-   (2E)-5-Methyl-5-(methylamino)hex-2-enoic acid    N-((1R)-1-{N-[(1R)-1-benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(biphenyl-4-yl)ethyl)-N-methylamide

-   (2E)-4-(1-Aminocyclobutyl)but-2-enoic acid    ((1R)-1-{N-[(1R)-1-benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(biphenyl-4-yl)ethyl)amide

and pharmaceutically acceptable salts thereof.

In another embodiment, the growth hormone secretagogue is represented bystructural Formula VI or a pharmaceutically acceptable salt, solvate orhydrate thereof. The chemical name for the compound represented bystructural Formula VI is: (2E)-4-(1-aminocyclobutyl)but-2-enoic acidN-((1R)-1-{N-[(1R)-1-benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]-N-methylcarbomoyl}-2-(biphenyl-4-yl)ethyl)-N-methylamide.

In yet another embodiment, the growth hormone secretagogue isrepresented by structural Formula VII or a pharmaceutically acceptablesalt, solvate or hydrate thereof. The chemical name of the compoundrepresented by structural Formula VII is:(2E)-5-amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-{N-methyl-N-[(1R)-2-phenyl-1-(N,N′,N′-trimethylhydrazinocarbonyl)ethyl]carbamoyl}-2-(2-naphthyl)ethyl)amide.

In one embodiment, the growth hormone secretagogue is represented bystructural Formula VIII or a pharmaceutically acceptable salt, solvateor hydrate thereof.

The chemical name of the compound represented by structural Formula VIIIis: (2E)-5-amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-{N-methyl-N-[(1R)-2-phenyl-1-(N,N′,N′-trimethylhydrazinocarbonyl)ethyl]carbamoyl}2-(2-naphthyl)ethyl)amide.

In another embodiment, the growth hormone secretagogue is represented bystructural Formula IX or a pharmaceutically acceptable salt, solvate orhydrate thereof. The chemical name for the compound represented bystructural Formula IX is:2-amino-N-(2-(2-(N-((2R)-2-(N-((2E)-5-amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-napthyl)propionyl)-N-methylamino)ethyl)phenyl)acetamide.

In further embodiments, the growth hormone secretagogue can be selectedfrom GHRP-1 (Formula X), GHRP-2 (Formula XI), GHRP-6 (Formula XII),NN703 (Formula XIII), Ipamorelin (Formula XIV), Capromorelin (FormulaXV) and MK-677 (Formula XVI) and analogs of any of the above.

Peripherally Acting Opioid Antagonists

Peripherally acting opioid receptor antagonists, such asmethylnaltrexone, naloxone, naltrexone, nalmefene and alvimopan(ENTEREG™), which do not cross the blood-brain barrier, can beadministered to treat opioid induced side effects without provokingopioid withdrawal symptoms or reverse analgesia. (Holzer P., “Opioidsand Opioid Receptors in the Enteric Nervous System: From a Problem inOpioid Analgesia to a Possible New Prokinetic Therapy in Humans,”Neurosci Lett., 361(1-3):192-5 (2004), incorporated herein byreference).

As used herein, peripherally acting opioid antagonists refer to opioidantagonists that act peripherally (i.e., not centrally, for example, donot act on the central nervous system).

Proton Pump Inhibitors

Proton pump inhibitors suppress gastric acid secretion, the final stepof acid production, by specific inhibition of the H⁺K⁺-ATPase enzymesystem at the secretory surface of gastric parietal cells. Proton pumpinhibitors include benzimidazole compounds, for example, esomeprazole(NEXIUM®), omeprazole (PRILOSEC™), lansoprazole (PREVACID™), andpantoprazole. These proton pump inhibitors contain a sulfinyl groupsituated between substituted benzimidazole and pyridine rings. Atneutral pH, esomeprazole, omeprazole, lansoprazole, and pantoprazole arechemically stable, lipid soluble, weak bases that are devoid ofinhibitory activity. These uncharged weak bases reach parietal cellsfrom the blood and diffuse into the secretory canaliculi, where thedrugs become protonated and thereby trapped. The protonated speciesrearranges to form a sulfenic acid and a sulfenamide, the latter speciescapable of interacting with sulfhydryl groups of H⁺K⁺-ATPase. Fullinhibition occurs with two molecules of inhibitor per molecule ofenzyme. The specificity of the effects of proton pump inhibitors isbelieved to derive from: a) the selective distribution of H⁺K⁺-ATPase;b) the requirement for acidic conditions to catalyze generation of thereactive inhibitor; and c) the trapping of the protonated drug and thecationic sulfenamide within the acidic canaliculi and adjacent to thetarget enzyme. Goodman & Gilman's The Pharmacological Basis ofTherapeutics, 9th Edition, pp. 901-915 (1996), incorporated herein byreference.

H₂ Antagonists

H₂ receptor antagonists competitively inhibit the interaction ofhistamine with H₂ receptors. They are highly selective and have littleor no effect on H₁ receptors. Although H₂ receptors are present innumerous tissues, including vascular and bronchial smooth muscle, H₂receptor antagonists interfere remarkably little with physiologicalfunctions other than gastric acid secretion. H₂ receptor antagonistsinclude, but are not limited to, nizatidine (AXID™), ranitidine (ZANTAC™and TRITEC™), famotidine (PEPCID AC™), and cimetidine (TAGAMET™) andrabeprazole (ACIPHEX™). Goodman & Gilman's The Pharmacological Basis ofTherapeutics, 9th Edition, pp. 901-915 (1996), incorporated herein byreference:

H₂ receptor antagonists inhibit gastric acid secretion elicited byhistamine, other H₂ agonists, gastrin, and, to a lesser extent,muscarinic agonists. H₂ receptor antagonists also inhibit basal andnocturnal acid secretion.

Antacids

Compounds of the invention can be administered with antacids toneutralize gastric acid. For example, aluminum and magnesium hydroxide(MAALOX™ and MYLANTA™) neutralize gastric acidity, resulting in increasein pH in the stomach and duodenal bulb.

Laxatives

Laxatives come in various forms: liquids, tablets, suppositories,powders, granules, capsules, chewing gum, chocolate-flavored wafers, andcaramels. The basic types of laxatives are bulk-forming laxatives,lubricant laxatives, stool softeners (also called emollient laxatives),and stimulant laxatives.

Bulk-Forming Laxatives

Bulk-forming laxatives contain materials, such as cellulose andpsyllium, that pass through the digestive tract without being digested.In the intestines, these materials absorb liquid and swell, making thestool soft, bulky, and easier to pass. The bulky stool then stimulatesthe bowel to move. Laxatives in this group include such brands asFIBERCON®, FIBERALL®, and METAMUCIL®.

Lubricant Laxatives

Mineral oil is the mostly widely used lubricant laxative. Taken bymouth, the oil coats the stool. This keeps the stool moist and soft andmakes it easier to pass. Lubricant laxatives are often used for patientswho need to avoid straining (e.g., after abdominal surgery).

Stool Softeners (Emollient Laxatives)

As their name suggests, stool softeners make stools softer and easier topass by increasing their moisture content. This type of laxative doesnot really stimulate bowel movements, but it makes it possible to havebowel movements without straining. Stool softeners are best used toprevent constipation in people who need to avoid straining, because ofrecent surgery, for example. Three stool-softening agents are available:docusate sodium (COLACE®, REGUTOL®, and others), docusate calcium(SURFAK®, DC SOFTGELS®) and docusate potassium (DIALOSE®, DIOCTO-K®).

Serotonin 5-HT₄ Agonist

The 5-HT₄ agonists speed up movement of bowel contents through the colonand reduces sensitivity to intestinal nerve stimulation. Suitableserotonin 5-HT₄ agonists which can be used in combination with thecompounds of the invention include sumatriptan, rauwolscine, yohimbine,metoclopramide, prucalopride and tegaserod (ZELNORM®). Spiller R.,“Serotonergic Modulating Drugs for Functional GastrointestinalDiseases,” Br J Clin Pharmacol. 54:11-20 (2002) and U.S. Pat. No.6,413,988, incorporated herein by reference.

Motilin Receptor Agonists

Motilin is a peptide of 22 amino acids which is produced in thegastrointestinal system of a number of species. Motilin induces smoothmuscle contractions in the stomach tissue of dogs, rabbits, and humansas well as in the colon of rabbits. Apart from local gastrointestinalintestinal tissues, motilin and its receptors have been found in othertissues.

Aside from motilin itself, there are other substances which are agonistsof the motilin receptor and which elicit gastrointestinal emptying. Oneof those agents is the antibiotic erythromycin. Studies have shown thaterythromycin elicits biological responses that are comparable to motilinitself and therefore can be useful in the treatment of diseases such aschronic idiopathic intestinal pseudo-obstruction and gastroparesis.Weber, F. et al., The American Journal of Gastroenterology, 88:4, 485-90(1993), incorporated herein by reference.

Dopamine Antagonists

Dopamine antagonists are drugs that bind to, but do not activate,dopamine receptors thereby blocking the actions of dopamine or exogenousagonists. This class of drugs includes, but are not limited to,bethanecol, metoclopramide, domperidone, amisulpride, clebopride,mosapramine, nemonapride, remoxipride, risperidone, sulpiride,sultopride and ziprasidone.

Cholinesterase Inhibitors

The term “cholinesterase inhibitor” refers to one or more agents thatprolong the action of acetylcholine by inhibiting its destruction orhydrolysis by cholinesterase. Cholinesterase inhibitors are also knownas acetylcholinesterase inhibitors. Examples of cholinesteraseinhibitors include, but are not limited to, edrophonium, neostigmine,neostigmine methylsulfate, pyridostigmine, tacrine and physostigmine,ambenonium chloride (MYTELASE®), edrophonium chloride (TENSILON®),neostigmine (PROSTIGMINE®), piridogstimina (MESTINON®), distigminebromide, eptastigmine, galanthamine, axeclidine, acetylcholine bromine,acetylcholine chloride, aclatonium napadisilate, benzpyrinium bromide,carbachol, carponium chloride, cemecarium bromide, dexpanthenol,diisopropyl paraoxon, echothiophate chloride, eseridine, furtrethonium,methacholine chloride, muscarine, oxapropanium idoide, and xanomeline.

Subject, as used herein, refers to animals such as mammals, including,but not limited to, primates (e.g., humans), cows, sheep, goats, horses,pigs, dogs, cats, rabbits, guinea pigs, rats, mice or other bovine,ovine, equine, canine, feline, rodent or murine species. In a preferredembodiment, the mammal is a human.

As used herein, treating and treatment refer to stimulating (e.g.,inducing) motility of the gastrointestinal system.

As used herein, therapeutically effective amount refers to an amountsufficient to elicit the desired biological response. In the presentinvention, the desired biological response is stimulating (e.g.,inducing) motility of the gastrointestinal system. In one embodiment,the desired biological response is stimulating (e.g., inducing) motilityof the gastrointestinal system to treat opioid induced constipation in asubject in need thereof. In another embodiment, the subject is usingopioids for post-surgical pain management. In yet another embodiment,the subject is using opioids for chronic pain management.

In one embodiment, the desired biological response is stimulating (e.g.,inducing) motility of the gastrointestinal system to treat diabetesrelated gastroparesis in a subject in need thereof.

In another embodiment, the desired biological response is stimulating(e.g., inducing) motility of the gastrointestinal system to treatgastroesophageal reflux disease in a subject in need thereof. In yetanother embodiment, the gastroesophageal reflux disease is nocturnalgastroesophageal reflux disease.

In one embodiment, the desired biological response is stimulating (e.g.,inducing) motility of the gastrointestinal system to treat irritablebowel syndrome in a subject in need thereof. In another embodiment theirritable bowel syndrome is constipation-predominant irritable bowelsyndrome. In yet another embodiment, the irritable bowel syndrome isconstipation/diarrhea irritable bowel syndrome.

In another embodiment, the desired biological response is stimulating(e.g., inducing) motility of the gastrointestinal system to treatconstipation in a subject in need thereof.

In another embodiment, the desired biological response is stimulating(e.g., inducing) motility of the gastrointestinal system to treatpost-operative ileus in a subject in need thereof.

The therapeutically effective amount or dose will depend on the age, sexand weight of the patient, and the current medical condition of thepatient. The skilled artisan will be able to determine appropriatedosages depending on these and other factors to achieve the desiredbiological response.

A suitable dose per day for the growth hormone secretagogue can be inthe range of from about 1 ng to about 10,000 mg, about 5 ng to about9,500 mg, about 10 ng to about 9,000 mg, about 20 ng to about 8,500 mg,about 30 ng to about 7,500 mg, about 40 ng to about 7,000 mg, about 50ng to about 6,500 mg, about 100 ng to about 6,000 mg, about 200 ng toabout 5,500 mg, about 300 ng to about 5,000 mg, about 400 ng to about4,500 mg, about 500 ng to about 4,000 mg, about 1 μg to about 3,500 mg,about 5 μg to about 3,000 mg, about 10 μg to about 2,600 mg, about 20 μgto about 2,575 mg, about 30 μg to about 2,550 mg, about 40 μg to about2,500 mg, about 50 μg to about 2,475 mg, about 100 μg to about 2,450 mg,about 200 μg to about 2,425 mg, about 300 μg to about 2,000, about 400μg to about 1,175 mg, about 500 μg to about 1,150 mg, about 0.5 mg toabout 1,125 mg, about 1 mg to about 1,100 mg, about 1.25 mg to about1,075 mg, about 1.5 mg to about 1,050 mg, about 2.0 mg to about 1,025mg, about 2.5 mg to about 1,000 mg, about 3.0 mg to about 975 mg, about3.5 mg to about 950 mg, about 4.0 mg to about 925 mg, about 4.5 mg toabout 900 mg, about 5 mg to about 875 mg, about 10 mg to about 850 mg,about 20 mg to about 825 mg, about 30 mg to about 800 mg, about 40 mg toabout 775 mg, about 50 mg to about 750 mg, about 100 mg to about 725 mg,about 200 mg to about 700 mg, about 300 mg to about 675 mg, about 400 mgto about 650 mg, about 500 mg, or about 525 mg to about 625 mg.

Other suitable doses per day for the growth hormone secretagogue includedoses of about or greater than 1 ng, about 5 ng, about 10 ng, about 20ng, about 30 ng, about 40 ng, about 50 ng, about 100 ng, about 200 ng,about 300 ng, about 400 ng, about 500 ng, about 1 μg, about 5 μg, about10 μg, about 20 μg, about 30 μg, about 40 μg, about 50 μg, about 100 μg,about 200 μg, about 300 μg, about 400 μg, about 500 μg (0.5 mg), about 1mg, about 1.25 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5 mg, about 10 mg,about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg,about 1125 mg, about 1150 mg, about 1175 mg, about 1200 mg, about 1225mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg,about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg,about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925mg, about 1950 mg, about 1975 mg, about 2000 mg, about 2025 mg, about2050 mg, about 2075 mg, about 2100 mg, about 2125 mg, about 2150 mg,about 2175 mg, about 2200 mg, about 2225 mg, about 2250 mg; about 2275mg, about 2300 mg, about 2325 mg, about 2350 mg, about 2375 mg, about2400 mg, about 2425 mg, about 2450 mg, about 2475 mg, about 2500 mg,about 2525 mg, about 2550 mg, about 2575 mg, about 2600 mg, about 3,000mg, about 3,500 mg, about 4,000 mg, about 4,500 mg, about 5,000 mg,about 5,500 mg, about 6,000 mg, about 6,500 mg, about 7,000 mg, about7,500 mg, about 8,000 mg, about 8,500 mg, about 9,000 mg, or about 9,500mg.

In a particular embodiment, a suitable dose of the growth hormonesecretagogue can be in the range of from about 0.20 mg to about 4000 mgper day, such as from about 1 mg to about 4000 mg, for example, fromabout 5 mg to about 3000 mg, such as about 10 mg to about 2400 mg perday. The dose can be administered in a single dosage or in multipledosages, for example from 1 to 4 or more times per day. When multipledosages are used, the amount of each dosage can be the same ordifferent.

A suitable dose for the additional therapeutic agent can be in samerange as described above for the growth hormone secretagogue. The doseof growth hormone secretagogue and additional agent can be the same ordifferent. Suitable doses for the additional agents can be found in theliterature.

Combination Administration

Administration of a growth hormone secretagogue can take place prior to,after or at the same time as treatment with an additional therapeuticagent, such as, for example, a laxative, a H₂ receptor antagonist, aserotonin 5-HT₄ agonist, an antacid, an opioid antagonist, a proton pumpinhibitor, or a combination thereof. The therapeutic agent can beadministered during the period of growth hormone secretagogueadministration but does not need to occur over the entire growth hormonesecretagogue treatment period.

Modes of Administration

The compounds for use in the method of the invention can be formulatedfor administration by any suitable route, such as for oral orparenteral, for example, transdermal, transmucosal (e.g., sublingual,lingual, (trans)buccal), vaginal (e.g., trans- and perivaginally),(intra)nasal and (trans)rectal), subcutaneous, intramuscular,intradermal, intra-arterial, intravenous, inhalation, and topicaladministration.

Suitable compositions and dosage forms include tablets, capsules,caplets, pills, gel caps, troches, dispersions, suspensions, solutions,syrups, granules, beads, transdermal patches, gels; powders, pellets,magmas, lozenges, creams, pastes, plasters, lotions, discs,suppositories, liquid sprays, dry powders or aerosolized formulations.

It is preferred that the compounds are orally administered. Suitableoral dosage forms include, for example, tablets, capsules or capletsprepared by conventional means with pharmaceutically acceptableexcipients such as binding agents (e.g., polyvinylpyrrolidone orhydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g., magnesium stearate,talc or silica); disintegrates (e.g., sodium starch glycollate); orwetting agents (e.g., sodium lauryl sulphate). If desired, the tabletscan be coated, e.g., to provide for ease of swallowing or to provide adelayed release of active, using suitable methods. Liquid preparationfor oral administration can be in the form of solutions, syrups orsuspensions. Liquid preparations (e.g., solutions, suspensions andsyrups) are also suitable for oral administration and can be prepared byconventional means with pharmaceutically acceptable additives such assuspending agents (e.g., sorbitol syrup, methyl cellulose orhydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia);non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol);and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbicacid).

As used herein, the term pharmaceutically acceptable salt refers to asalt of a compound to be administered prepared from pharmaceuticallyacceptable non-toxic acids including inorganic acids, organic acids,solvates, hydrates, or clathrates thereof. Examples of such inorganicacids are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, andphosphoric. Appropriate organic acids may be selected, for example, fromaliphatic, aromatic, carboxylic and sulfonic classes of organic acids,examples of which are formic, acetic, propionic, succinic,camphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, malic,mucic, tartaric, para-toluenesulfonic, glycolic, glucuronic, maleic,furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic,mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic,pantothenic, benzenesulfonic (besylate), stearic, sulfanilic, alginic,galacturonic, and the like.

The growth hormone secretagogues disclosed can be prepared in the formof their hydrates, such as hemihydrate, monohydrate, dihydrate,trihydrate, tetrahydrate and the like and as solvates.

It is understood that growth hormone secretagogue compounds can beidentified, for example, by screening libraries or collections ofmolecules using suitable methods. Another source for the compounds ofinterest are combinatorial libraries which can comprise manystructurally distinct molecular species. Combinatorial libraries can beused to identify lead compounds or to optimize a previously identifiedlead. Such libraries can be manufactured by well-known methods ofcombinatorial chemistry and screened by suitable methods.

Stereochemistry

Many of the compounds described herein can have one or more chiralcenters and therefore can exist in different enantiomeric forms. Ifdesired, a chiral carbon can be designated with an asterisk (*). Whenbonds to the chiral carbon are depicted as straight lines in theformulas of the invention, it is understood that both the (R) and (S)configurations of the chiral carbon, and hence both enantiomers andmixtures thereof, are embraced within the formula. As is used in theart, when it is desired to specify the absolute configuration about achiral carbon, one of the bonds to the chiral carbon can be depicted asa wedge (bonds to atoms above the plane) and the other can be depictedas a series or wedge of short parallel lines is (bonds to atoms belowthe plane). The Cahn-Inglod-Prelog system can be used to assign the (R)or (S) configuration to a chiral carbon.

When a compound of the present invention has two or more chiral carbons,it can have more than two optical isomers and can exist indiastereoisomeric forms. For example, when there are two chiral carbons,the compound can have up to 4 optical isomers and 2 pairs of enantiomers((S,S)/(R,R) and (R,S)/(S,R)). The pairs of enantiomers (e.g.,(S,S)/(R,R)) are mirror image stereoisomers of one another. Thestereoisomers which are not mirror-images (e.g., (S,S) and (R,S)) arediastereomers. The diastereoisomeric pairs may be separated by methodsknown to those skilled in the art, for example chromatography orcrystallization and the individual enantiomers within each pair may beseparated as described above. The present invention includes eachdiastereoisomer of such compounds and mixtures thereof.

Variable Definitions

In the above structural formulas and throughout the presentspecification, the following terms have the indicated meanings:

The C₁₋₆-alkyl, C₁₋₆-alkylene, C₁₋₄-alkyl or C₁₋₄-alkylene groupsspecified above are intended to include those alkyl or alkylene groupsof the designated length in either a linear or branched or cyclicconfiguration as permitted. Examples of linear alkyl are methyl, ethyl,propyl, butyl, pentyl, and hexyl and their corresponding divalentmoieties, such as ethylene. Examples of branched alkyl are isopropyl,sec-butyl, tert-butyl, isopentyl, and isohexyl and their correspondingdivalent moieties, such as isopropylene. Examples of cyclic alkyl areC₃₋₆-cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl and their corresponding divalent moieties, such ascyclopropylene.

The C₁₋₆-alkoxy groups specified above are intended to include thosealkoxy groups of the designated length in either a linear or branched orcyclic configuration. Examples of linear alkoxy are methoxy, ethoxy,propoxy, butoxy, pentoxy, and hexoxy. Examples of branched alkoxy areisopropoxy, sec-butoxy, tert-butoxy, isopentoxy, and isohexoxy. Examplesof cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy andcyclohexyloxy.

The C₁₋₇-acyl groups specified above are intended to include those acylgroups of the designated length in either a linear or branched or cyclicconfiguration. Examples of linear acyl are formyl, acetyl, propionyl,butyryl, valeryl, etc. Examples of branched are isobutyryl, isovaleryl,pivaloyl, etc. Examples of cyclic are cyclopentylcarbonyl,cyclohexylcarbonyl, etc.

In the present context, the term “aryl” is intended to includemonovalent carbocyclic aromatic ring moieties, being either monocyclic,bicyclic or polycyclic, e.g., phenyl and napthyl, optionally substitutedwith one or more C₁₋₆alkyl, C₁₋₆alkoxy, halogen, amino or aryl.

In the present context, the term “arylene” is intended to includedivalent carbocyclic aromatic ring moieties, being either monocyclic,bicyclic or polycyclic, e.g. selected from the group consisting ofphenylene and napthylene, optionally substituted with one or moreC₁₋₆alkyl, C₁₋₆alkoxy, halogen, amino or aryl.

In the present context, the term “hetaryl” is intended to includemonovalent heterocyclic aromatic ring moieties, being either monocyclic,bicyclic or polycyclic, e.g. selected from the group consisting ofpyridyl, 1-H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl,thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl,quinolinyl, pyrazinyl, or isothiazolyl, optionally substituted by one ormore C₁₋₆alkyl, C₁₋₆alkoxy, halogen, amino or aryl.

In the present context, the term “hetarylene” is intended to includedivalent heterocyclic aromatic ring moieties, being either monocyclic,bicyclic or polycyclic, e.g. selected from the group consisting ofpyridinediyl, 1-H-tetrazolediyl, imidazolediyl, indolediyl,pyrimidinediyl, thiadiazolediyl, pyrazolediyl, oxazolediyl,isoxazolediyl, oxadiazolediyl, thiophenediyl, quinolinediyl,pyrazinediyl, or isothiazolediyl, optionally substituted by one or moreC₁₋₆alkyl, C₁₋₆alkoxy, halogen, amino or aryl.

In the present context, the term “heterocyclic system” is intended toinclude aromatic as well as non-aromatic ring moieties, which may bemonocyclic, bicyclic or polycyclic, and contain in their ring structureat least one, such as one, two or three, nitrogen atom(s), andoptionally one or more, such as one or two, other hetero atoms, e.g.sulphur or oxygen atoms. The heterocyclic system is preferably selectedfrom pyrazole, pyridazine, triazine, indazole, phthalazine, cinnoline,pyrazolidine, pyrazoline, aziridine, dithiazine, pyrrol, imidazol,pyrazole, isoindole, indole, indazole, purine, pyrrolidine, pyrroline,imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine,piperazine, indoline, isoindoline, or morpholine.

The term “halogen” is intended to include chlorine (Cl), fluorine (F),bromine (Br) and iodine (I).

Exemplification

The present invention will now be illustrated by the following Example,which are not intended to be limiting in any way.

Study in Rat Model

The experiment was conducted to determine the prokinetic effect of thegrowth hormone secretagogue RC-1139. The compound RC-1139 was tested innormal conscious animals, as well as in the post-operative period,including concomitant morphine administration, to mimic the clinicalcondition where most post-operative patients are receiving opiateanalgesia that can contribute to or increase post-operativegastrointestinal ileus.

Study Design

Normal Conscious Rats

Gastric emptying in healthy rats was studied. A total of eighteen (n=18)animals were administered RC-1139 (six animals (n=6)/group). Animalswere administered a distilled water solution (1.5 ml) containing 1.5%methylcellulose and technitium-99m (^(99m)Tc) (approximately 100,000counts per minute) administered intragastrically through stainless steeltube in conscious rats. Ten (n=10) control animals were administered themethylcellulose solution but saline instead of RC-1139. The substancestested (saline vs. RC-1139) were injected intravenously at the end ofthe methylcellulose administration at time 0. The dose levels of RC-1139were as follows: 0.25, 1.0 and 2.5 mg/kg. RC-1139 was given as a 1 minbolus and was well tolerated at all doses.

Gastric emptying was measured by the following technique. Animals weresacrificed by CO₂ inhalation and after 15 min and the abdomen wasopened. Stomachs were clamped at the pylorus and cardia were removed andplaced in test tubes for counting with the use of a gamma counter theamount of radioactivity left in the stomach. The results are shown inFIG. 1.

Post-Operative Ileus

Post-operative ileus was studied in nine (n=9) animals/group. Gastricileus was induced as follows: the rats were anesthetized with isofluraneand submitted to laparotomy. The cecum was exteriorized and gentlymanipulated (patted between hands for 1 minute in saline-soaked gauze).Abdominal muscles were then closed with silk sutures and the animalswere allowed to recover for 5 minutes before gavage for gastric emptyingstudies. A distilled water solution (1.5 ml) containing 1.5%methylcellulose and technitium-99m (^(99m)Tc) (approximately 100,000counts per minute) was then administered intragastrically throughstainless steel tube in conscious rats. The substances tested (salinevs. RC-1139) were injected intravenously at the end of themethylcellulose administration at time 0. The dose levels of RC-1139were as follows: 1.0, 2.5 and 10 mg/kg. RC-1139 was given as a 1 minbolus and was well tolerated at all doses.

Gastric emptying was measured by the following technique. Animals weresacrificed by CO₂ inhalation after 15 min and the abdomen was opened.Stomachs were clamped at the pylorus and cardia were removed and placedin test tubes for counting with the use of a gamma counter the amount ofradioactivity left in the stomach. The results are shown in FIG. 2.

Post-Operative Ileus and Morphine

To study opiate analgesia induced post-operative ileus, eight (n=8)rats/group were administered morphine (4 mg/kg) thirty minutes (30 min)before methylcellulose administration. As described above, gastric ileuswas induced by submitting the rats to laparotomy after anesthesia withisoflurane. The cecum was exteriorized and gently manipulated (pattedbetween hands for 1 minute in saline-soaked gauze). Abdominal muscleswere then closed with silk sutures and the animals were allowed torecover for 5 minutes before gavage for gastric emptying studies. Adistilled water solution (1.5 ml) containing 1.5% methylcellulose andtechnitium-99m (^(99m)Tc) (approximately 100,000 counts per minute) wasthen administered intragastrically through stainless steel tube inconscious rats. The substances tested (saline vs. RC-1139) were injectedintravenously at the end of the methylcellulose administration at time0. The dose levels were as follows: 2.5, 10 and 50 mg/kg. RC-1139 wasgiven as a 1 min bolus and was well tolerated at all doses.

Gastric emptying was measured by the following technique. Animals werekilled by CO₂ inhalation after 15 mm and the abdomen was opened.Stomachs were clamped at the pylorus and cardia were removed and placedin test tubes for counting with the use of a gamma counter the amount ofradioactivity left in the stomach. The results are shown in FIG. 3.

In order to study a situation in which an opiate would be overdosed, anexperiment was conducted in rats with induced post-operative ileus asdiscussed above, however, the dose of morphine was 12 mg/kg. The resultsare shown in FIG. 4.

An experiment was also conducted in normal conscious rats as discussedabove at both 4 mg/kg of morphine (FIG. 5) and 12 mg/kg of morphine(FIG. 6).

Study Endpoints

To assess gastric emptying, gastric residue remaining in the stomach wasmeasured 15 min postingestion of the methycellulose solution by countingthe amount of ^(99m)Tc in the removed organ. Data expressed inpercentage of the administered dose are shown as means±SEM. Statisticalanalysis was done by ANOVA (with Tukey-Kramer post-tests with one-to-onecomparisons).

Results

Normal Conscious Rats

After 15 min, 47.1±6.6% of the administered methylcellulose was left inthe stomach (n=10). In animals (n=6) treated with RC-1139, at doses of0.25, 1, 2.5 mg/kg, the amount of the methylcellulose left in thestomach was decreased respectively to 36±8.6 (p=NS), 11.9±3.6 (p<0.01)and 10.5±3.8 (p<0.01).

Post-Operative Ileus

In saline treated animals, gastric emptying was delayed since 88±2.5% ofthe administered methylcellulose was left in the stomach after 15 min.Animals (n=9) treated with RC-1139 at a dose of 1 mg/kg I.V. had a smallnon-significant decrease in their gastric residue (66.3±7.4%); whenRC-1139 was given at a dose of 2.5 or 10 mg/kg I.V., gastric emptyingwas accelerated and restored to normal values (52.9±9.2 and 50.7±6.2% ofgastric residue respectively; p<0.01).

Post-Operative Ileus and Morphine

Gastric emptying was slow in saline treated animals (n=8) (75.4±4.5% ofresidue) and this effect was not reversed by RC-1139 given at 2.5 mg/kg(69.4±5.3%), a dose that, as shown above, has been found effective toreverse post-operative ileus in absence of morphine. A higher dose ofRC-1139 (10 mg/kg) was required to reverse opiate analgesia inducedpost-operative gastrointestinal ileus to normal emptying values(53.8±4.8%; p<0.05). A larger dose of 50 mg/kg provided no furtherimprovement (59.5±8.5%).

In the experiment where an opiate overdose was mimicked in rats withinduced post-operative ileus and 12 mg/kg of morphine, RC-1139 given at10 mg/kg I.V. was unable to accelerate the delayed gastric emptyingfound in saline treated animals (75.7±3.3 vs. 75.1±4.9%; p=NS; n=6animals/group).

In the experiment in normal conscious rats administered 4 mg/kg ofmorphine and 12 mg/kg of morphine, morphine was a strong inhibitor ofgastric emptying in these animals (n=6/group). With the high dose ofmorphine (12 mg/kg), RC-1139 given at 2.5 or 10 mg/kg failed toaccelerate the delayed gastric emptying (92.6±3.2 vs. 79.5±2.4 or79.7±5.9%; p=NS). With the lower dose of morphine (4 mg/kg), the gastricresidue (99.1±0.5%) could be decreased to 77±4.1 or 71.3±6.7% by RC-1139at a dose of 2.5 mg/kg or 10 mg/kg respectively (p<0.01 for both); thesevalues however were still higher than the normal gastric emptying foundin normal basal conditions.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1-75. (canceled) 76) A method of treating post-operative ileus in apatient in need thereof, comprising administering to said patient atherapeutically effective amount of ipamorelin or a pharmaceuticallyacceptable salt thereof. 77) The method of claim 76 wherein saidpost-operative ileus is induced via opioid use and gastrointestinalsurgery. 78) The method of claim 76 comprising injection administration.79) The method of claim 76, wherein said treatment consists essentiallyof said administration. 80) The method of claim 76 comprisingadministration of from 0.01-2,600 mg of ipamorelin per day. 81) A methodof stimulating gastrointestinal motility in a patient in need thereof,comprising administering to said patient a therapeutically effectiveamount of ipamorelin or a pharmaceutically acceptable salt thereof. 82)The method of claim 81 comprising injection administration. 83) Themethod of claim 81 wherein said treatment consists essentially of saidadministration. 84) The method of claim 81 comprising administration offrom 0.01-2,600 mg of ipamorelin per day. 85) The method of claim 81wherein said patient is recovering from abdomen surgery. 86) The methodof claim 86 comprising administration of from 0.01-2,600 mg ofipamorelin per day. 87) The method of claim 86 wherein said patient isrecovering from abdomen surgery.